Brief Genetics Report Evidence for Gene-Nutrient Interaction at the PPARg Locus

The importance of the nuclear receptor peroxisome proliferator–activated receptor-g (PPARg) in regulating insulin resistance and blood pressure has been demonstrated in families with loss of function mutations. Gain of function mutations has been associated with severe obesity. However, previous population studies of the common variant Pro12Ala have produced conflicting results. As it is likely that the natural ligands for this receptor may include fatty acids, we hypothesized that the effect of this common variant may be altered by the character of the diet, particularly the ratio of dietary polyunsaturated fat to saturated fat (P:S ratio). We studied 592 nondiabetic participants in an ongoing population-based cohort study who were genotyped for the Pro12Ala polymorphism in the PPAR g2 isoform. As the Ala homozygotes were uncommon (2.0%), all analyses were conducted comparing Pro homozygotes (79.1%) to Ala allele carriers. There was no difference in fasting insulin concentration or BMI between Ala allele carriers and Pro homozygotes. The fasting insulin concentration was negatively associated with the P:S ratio (P 5 0.0119) after adjustment for age and sex, and a strong interaction was evident between the P:S ratio and the Pro12Ala polymorphism for both BMI (P 5 0.0038) and fasting insulin (P 5 0.0097). The data suggest that when the dietary P:S ratio is low, the BMI in Ala carriers is greater than that in Pro homozygotes, but when the dietary ratio is high, the opposite is seen. This gene-nutrient interaction emphasizes the difficulty of examining the effect of common polymorphisms in the absence of data on nongenetic exposures, and may explain the heterogeneity of findings in previous studies. Diabetes 50:686–689, 2001 A complete understanding of the etiology of common complex diseases such as diabetes, ischemic heart disease, and obesity will require exploration of the interactions between environmental factors and common genetic variants (1). To date, few examples of such interactions have been described. We present evidence for an environment-gene interaction influencing BMI and insulin sensitivity involving the nuclear receptor peroxisome proliferator–activated receptor-g (PPARg) and the pattern of dietary fat intake. A critical role for PPARg in the development of mammalian adipose tissue has been confirmed by the absence of adipose tissue in PPARg null murine embryos (2). Additionally, the importance of PPARg in the control of human insulin sensitivity and blood pressure has recently been established by the finding of severe insulin-resistant diabetes and early-onset hypertension in two families with loss of function mutations in this gene (3). A gain of function mutation in PPARg has also been reported in three subjects with severe obesity (4). Several studies have examined the relationship between a common variant (Pro12Ala) in the PPARg isoform (5) and metabolic variables (6–11). In terms of adiposity, studies have had variable results with some reporting increased (6), some decreased (7,8), and some neutral effects on BMI (9–11). The natural ligands for PPARg have yet to be definitively identified. While PGd15J2 is a potent activator of PPARg (12), it is uncertain whether this prostanoid exists in appreciable concentrations in vivo. Kliewer et al. (12) and Desvergne and Wahli (13) have suggested that a single specific ligand may not exist and that PPARg may be a fatty acid sensor, with the affinity of fatty acids for the receptor varying according to their chain length and degree of desaturation. Given the potential role of PPARg as a nutrient sensor regulating adipogenesis and insulin sensitivity, we have examined the interaction between the ratio of dietary polyunsaturated fat to saturated fat (P:S ratio) and the Pro12Ala polymorphism in a large U.K. Caucasian population. The Isle of Ely Study (14,15) is a prospective populationbased cohort study of the etiology and pathogenesis of type 2 diabetes and related metabolic disorders. A total of 592 nondiabetic Caucasian subjects (mean age 53.9 6 10.9 years, 259 men and 333 women) were genotyped for the From the Departments of Public Health and Primary Care and Medicine and Clinical Biochemistry, University of Cambridge, Cambridge, U.K. Address correspondence and reprint requests to Nicholas J. Wareham, MB, PhD, Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge CB2 2SR, U.K E-mail: [email protected]. Received for publication 1 August 2000 and accepted in revised form 6 November 2000. J.L. and P.O.B. contributed equally to this work. PCR, polymerase chain reaction; PPARg, peroxisome proliferator–activated receptor-g; P:S ratio; polyunsaturated:saturated fat ratio.